{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T17:06:31Z","timestamp":1773335191301,"version":"3.50.1"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T00:00:00Z","timestamp":1773273600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003653","name":"Korea National Institute of Health","doi-asserted-by":"publisher","award":["2021-NI-023-02"],"award-info":[{"award-number":["2021-NI-023-02"]}],"id":[{"id":"10.13039\/501100003653","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003653","name":"Korea National Institute of Health","doi-asserted-by":"publisher","award":["2025-NI-006-00"],"award-info":[{"award-number":["2025-NI-006-00"]}],"id":[{"id":"10.13039\/501100003653","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Methionine sulfoxide reductase B2 (MsrB2), a mitochondrial redox enzyme essential for maintaining protein integrity under oxidative stress, has been implicated in diabetic cardiac remodeling. However, its contribution to hypertension-induced fibrosis remains unclear. Hypertension frequently coexists with diabetes and accelerates cardiac fibrotic remodeling, particularly in non-obese diabetic patients who may exhibit distinct metabolic and oxidative responses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We investigated the role of MsrB2 in extracellular matrix (ECM)-driven cardiac fibrosis using both animal and human hypertensive heart samples. MsrB2 expression was evaluated in non-obese (Goto-Kakizaki, GOTO) and obese (OLETF) diabetic rat models and in angiotensin II (Ang II)\u2013infused MsrB2 knockout (KO) mice. Histological, biochemical, and transcriptomic analyses were performed to assess myocardial fibrosis, fibrosis-related signaling, and redox gene expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MsrB2 expression was markedly reduced in human hypertensive hearts and in the myocardium of non-obese diabetic rats, whereas it remained unchanged in obese diabetes despite similar increases in blood pressure. In MsrB2 KO mice, Ang II infusion provoked extensive interstitial and perivascular collagen deposition, accompanied by enhanced SMAD2\/3 activation and upregulation of profibrotic ECM genes including\n                      <jats:italic>Col1a1<\/jats:italic>\n                      ,\n                      <jats:italic>Col3a1<\/jats:italic>\n                      ,\n                      <jats:italic>COMP<\/jats:italic>\n                      , and\n                      <jats:italic>LOX<\/jats:italic>\n                      . Transcriptomic profiling revealed strong enrichment of extracellular matrix and collagen-related pathways, along with increased expression of oxidative\/inflammatory mediators such as\n                      <jats:italic>Spp1<\/jats:italic>\n                      and\n                      <jats:italic>Ccr2<\/jats:italic>\n                      , while antioxidant and mitochondrial quality-control genes (\n                      <jats:italic>Sdhaf2<\/jats:italic>\n                      ,\n                      <jats:italic>Rnls<\/jats:italic>\n                      ,\n                      <jats:italic>Mapk8<\/jats:italic>\n                      ) were suppressed. These results indicate that MsrB2 deficiency shifts the myocardium toward a pro-oxidant and pro-fibrotic phenotype under hypertensive stress.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Loss of MsrB2 amplifies ECM-driven cardiac fibrosis during hypertensive stress by promoting oxidative imbalance and SMAD2\/3 activation. In non-obese diabetes, the concomitant reduction of MsrB2 expression may further accelerate hypertensive remodeling, highlighting a mechanism that could explain the higher incidence of cardiovascular complications observed in non-obese diabetic individuals. These findings identify MsrB2 as a critical redox regulator that restrains ECM-driven fibrosis and suggest that enhancing its activity could represent a therapeutic approach to prevent metabolic and hypertensive cardiac disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphys.2026.1772933","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T05:28:59Z","timestamp":1773293339000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["MsrB2 deficiency amplifies ECM-driven cardiac fibrosis under hypertensive stress"],"prefix":"10.3389","volume":"17","author":[{"given":"Ji Ho","family":"Yun","sequence":"first","affiliation":[{"name":"Division of Endocrine and Kidney Disease Research, Department for Chronic Disease Convergence Research, Korea National Institute of Health (KNIH)","place":["Cheongju, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suyeon","family":"Cho","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Disease Research, Department for Chronic Disease Convergence Research, Korea National Institute of Health (KNIH)","place":["Cheongju, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jong Youl","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Disease Research, Department for Chronic Disease Convergence Research, Korea National Institute of Health (KNIH)","place":["Cheongju, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suji","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Disease Research, Department for Chronic Disease Convergence Research, Korea National Institute of Health (KNIH)","place":["Cheongju, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seung Hee","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Endocrine and Kidney Disease Research, Department for Chronic Disease Convergence Research, Korea National Institute of Health (KNIH)","place":["Cheongju, Republic of Korea"]},{"name":"Division of Cardiovascular Disease Research, Department for Chronic Disease Convergence Research, Korea National Institute of Health (KNIH)","place":["Cheongju, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.biochi.2017.08.012","article-title":"Genomic regulation of type 2 diabetes endophenotypes: contribution from genetic studies in the goto-kakizaki rat","volume":"143","author":"Bihoreau","year":"2017","journal-title":"Biochimie"},{"key":"B2","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1016\/j.bioorg.2014.07.002","article-title":"Methionine sulfoxide reductase: chemistry, substrate binding, recycling process and oxidase activity","volume":"57","author":"Boschi-Muller","year":"2014","journal-title":"Bioorg Chem."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1016\/j.bbapap.2014.01.001","article-title":"The physiological role of reversible methionine oxidation","volume":"1844","author":"Drazic","year":"2014","journal-title":"Biochim. 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